Overexpression of A20 promotes liver regeneration (LR), but contribution of physiologic A20 to LR remains unclear. We performed 2/3 partial hepatectomy (PH) in A20 heterozygous (HET) mice, provoking a drastic 42% lethality. Lethality resulted from enhanced inflammation and impaired regeneration associated with decreased Cyclins D1 and E, and increased Cyclin Dependent Kinase Inhibitor p21 expression. A20 knockdown minimally affected baseline liver transcriptome (<90 genes), mostly showing differential expression of circadian rhythm regulated genes, while over 1,000 genes were differentially expressed post-PH in a way that promoted inflammation, decreased proliferation, and hindered lipid metabolism. To determine the molecular basis for partial A20 knockdown dramatically influencing the liver regenerative response following PH, we constructed a feed-forward transcriptionally interactive two-layered network consisting of genes differentially expressed prior to PH that interacted with at least 2 genes after PH. This identified key differentially expressed hub genes before PH including regulators of: circadian rhythm, i.e. Aryl hydrocarbon receptor nuclear translocator like, Neuronal PAS domain-containing protein 2, and D site of albumin promoter binding protein; cell cycle, i.e. Cyclin D1 and tubulin beta 2A; and lipid and glucose metabolism, i.e. insulin induced regulator of SREBP1c, regulator of G-coupled receptor signaling 16, and pryrruvate dehydrogenase kinase isozyme 4. The second (post-PH) layer mainly consisted of genes involved in lipid metabolism that were negatively affected by A20 knockdown. Consequently, A20 HET mice had significantly higher intra-hepatic levels of triglycerides and displayed exagerated macrosteatosis (oil red-O staining) in their livers following PH, when compared to wild type mice.

Collectively, these data uncover a distinct phenotype in A20 HET mice, whereby subtle deregulation of liver circadian rhythm negatively impacts LR, promoting death. This is particularly significant given newly reported A20 gene polymorphisms that, by decreasing A20’s expression or function, could negatively affect outcome of extensive liver resection for donation or tumor.

« Back to 2013 American Transplant Congress